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Impaired incretin homeostasis in non-diabetic moderate to severe chronic kidney disease
Abstract
Background: Incretins are regulators of insulin secretion and glucose homeostasis metabolized by dipeptidyl peptidase-4 (DPP-4). Chronic kidney disease (CKD) may modify incretin release, metabolism, or response. Methods: We performed two-hour oral glucose tolerance testing (OGTT) in 59 people with nondiabetic CKD (estimated glomerular filtration rate [GFR]<60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental area under the curve (iAUC) of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors. Results: Mean (standard deviation [SD]) eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2 in CKD and controls, respectively. GLP-1 tAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ± 1452 versus 1364 ± 1484 pMxmin, and 62370 ± 33453 versus 42365 ± 25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% confidence intervals [CI]: 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI: -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI: 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI: 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups. Conclusions: Overall, incretin response to oral glucose is preserved or augmented in moderate to severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.
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